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- PDB-8dvl: Crystal structure of LRP6 E3E4 in complex with disulfide constrai... -

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Basic information

Entry
Database: PDB / ID: 8dvl
TitleCrystal structure of LRP6 E3E4 in complex with disulfide constrained peptide E3.18
Components
  • E3.18 Disulfide constrained peptide
  • Low-density lipoprotein receptor-related protein 6
KeywordsSIGNALING PROTEIN / LRP6 / E3E4 / Wnt Signaling / Disulfide constrained peptide / Wnt agonism
Function / homology
Function and homology information


Wnt-Frizzled-LRP5/6 complex / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / neural crest formation / Signaling by RNF43 mutants / kinase inhibitor activity / toxin transmembrane transporter activity / Wnt receptor activity / low-density lipoprotein particle receptor activity / Wnt-protein binding / cellular response to cholesterol ...Wnt-Frizzled-LRP5/6 complex / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / neural crest formation / Signaling by RNF43 mutants / kinase inhibitor activity / toxin transmembrane transporter activity / Wnt receptor activity / low-density lipoprotein particle receptor activity / Wnt-protein binding / cellular response to cholesterol / midbrain dopaminergic neuron differentiation / dopaminergic neuron differentiation / frizzled binding / Wnt signalosome / Disassembly of the destruction complex and recruitment of AXIN to the membrane / neural crest cell differentiation / negative regulation of smooth muscle cell apoptotic process / protein serine/threonine kinase inhibitor activity / canonical Wnt signaling pathway / coreceptor activity / positive regulation of cell cycle / Regulation of FZD by ubiquitination / TCF dependent signaling in response to WNT / protein localization to plasma membrane / cell-cell adhesion / response to peptide hormone / Wnt signaling pathway / endocytosis / nervous system development / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / early endosome membrane / chemical synaptic transmission / membrane raft / signaling receptor binding / neuronal cell body / synapse / positive regulation of DNA-templated transcription / cell surface / endoplasmic reticulum / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Low density lipoprotein receptor-related protein 5/6 / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. ...Low density lipoprotein receptor-related protein 5/6 / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / Epidermal growth factor-like domain. / EGF-like domain signature 2. / EGF-like domain
Similarity search - Domain/homology
Low-density lipoprotein receptor-related protein 6
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsThakur, A.K. / Liau, N.P.D. / Sudhamsu, J. / Hannoush, R.N.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Chem.Biol. / Year: 2023
Title: Synthetic Multivalent Disulfide-Constrained Peptide Agonists Potentiate Wnt1/ beta-Catenin Signaling via LRP6 Coreceptor Clustering.
Authors: Thakur, A.K. / Miller, S.E. / Liau, N.P.D. / Hwang, S. / Hansen, S. / de Sousa E Melo, F. / Sudhamsu, J. / Hannoush, R.N.
History
DepositionJul 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Low-density lipoprotein receptor-related protein 6
B: E3.18 Disulfide constrained peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,24817
Polymers75,0362
Non-polymers3,21115
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5830 Å2
ΔGint29 kcal/mol
Surface area27340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.911, 73.835, 87.193
Angle α, β, γ (deg.)90.000, 96.580, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein Low-density lipoprotein receptor-related protein 6 / LRP-6


Mass: 71774.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRP6 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O75581
#2: Protein/peptide E3.18 Disulfide constrained peptide


Mass: 3261.798 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Sugars , 4 types, 5 molecules

#3: Polysaccharide alpha-L-fucopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)]2-acetamido-2-deoxy-beta- ...alpha-L-fucopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-3[DGlcpNAcb1-4]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2-1/a3-b1_a4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(3+1)][a-L-Fucp]{}[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#5: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 24 molecules

#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#8: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.47 Å3/Da / Density % sol: 50.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.3 / Details: 0.1 M Bis-Tris 6.3, 18% PEG 10K

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Oct 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 2.5→45.58 Å / Num. obs: 25374 / % possible obs: 99.69 % / Redundancy: 3.4 % / CC1/2: 0.998 / CC star: 1 / Net I/σ(I): 13.87
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.7 % / Num. unique obs: 2515 / CC1/2: 0.685 / CC star: 0.902 / % possible all: 99.92

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Processing

Software
NameVersionClassification
PHENIX1.20rc3-4406_finalrefinement
PDB_EXTRACT3.27data extraction
XSCALEdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4A0P

4a0p


Resolution: 2.5→45.58 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.11 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2454 3773 7.82 %
Rwork0.1972 44471 -
obs0.201 25374 96.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 144.39 Å2 / Biso mean: 63.0306 Å2 / Biso min: 31.32 Å2
Refinement stepCycle: final / Resolution: 2.5→45.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4964 0 207 14 5185
Biso mean--87.89 55.98 -
Num. residues----624
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5-2.530.37251370.36821607174496
2.53-2.560.4531340.33951642177697
2.56-2.60.35871430.3331682182597
2.6-2.630.39251400.30181672181297
2.63-2.670.29351300.28671551168194
2.67-2.710.3321350.29121569170493
2.71-2.760.31191430.26481681182496
2.76-2.810.32331420.25891605174797
2.81-2.860.29651400.2441692183297
2.86-2.910.30951450.23951652179798
2.91-2.970.26811400.23511610175098
2.97-3.040.25951450.25311711185698
3.04-3.110.33381410.25611670181198
3.11-3.180.38411440.22791647179198
3.18-3.270.25471400.21631649178997
3.27-3.370.24541410.20571680182197
3.37-3.480.28931400.19591666180698
3.48-3.60.28521380.18431662180098
3.6-3.740.25231380.21041621175996
3.74-3.910.25151460.19081680182696
3.91-4.120.22981410.1681648178997
4.12-4.380.16121350.16051602173796
4.38-4.720.16211420.13861640178295
4.72-5.190.17761280.14921579170793
5.19-5.940.21771410.1891673181499
5.94-7.480.23671420.172816921834100
7.48-45.580.21481420.1671688183099
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.33550.096-0.69381.57580.74973.85910.0470.0528-0.0506-0.1286-0.04920.1249-0.0987-0.55380.00710.3528-0.0363-0.04940.4368-0.030.426112.5641-24.466-7.2175
21.73530.3798-0.2152.1770.16272.3971-0.0029-0.04750.13490.2364-0.02190.1463-0.1067-0.38160.03270.35830.05560.00830.31510.0070.323913.531-1.207531.665
31.91080.0944-0.35355.02153.03895.96191.09540.27750.65580.0263-0.2222-0.9014-1.34071.0317-0.74210.577-0.20990.19660.7133-0.13480.780730.7154-19.9378-2.8654
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 630 through 920 )A630 - 920
2X-RAY DIFFRACTION2chain 'A' and (resid 921 through 1246 )A921 - 1246
3X-RAY DIFFRACTION3chain 'B' and (resid 1 through 14 )B1 - 14

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